Bone Signaling And RANKL

Question 1

Bone resorption is performed by an active osteoclast. Osteoclasts are stimulated by: (list 2)

Answer 1

• RANKL in normal process

- PTH in pathologic process (metastatic disease)

Question 2

OPG inhibits:

Answer 2

Osteoclasts

Question 3

List 7 molecules that stimulate bone resorption

Answer 3

• RANKL
• PTH
• Interleukin 1 (IL-1)
• 1,25 dihydroxy vitamin D
• prostaglandin E2
• IL-6 (myeloma)
• MIP-1A (myeloma)

Question 4

What is the MOA of RANKL?

Answer 4

RANKL (ligand) is secreted by osteoblasts and binds to the RANK receptor on osteoclast precursor and mature osteoclast cells, stimulating them

Question 5

What is the MOA of PTH in relation to bone metabolism?

Answer 5

• PTH (secreted by many cancer cells) receptor activation stimulates the adenylyl cyclase pathway in osteocytes
• PTH bonds to cell surface receptors on osteoblasts to stimulate production of RANKL and M-CSF

Question 6

What is the MOA of IL-1 on bone metabolism?

Answer 6

IL-1 stimulates osteoclast differentiation, and thus bone resorption.

Question 7

What is the MOA of 1,25 dihydroxy Vitamin D on bone metabolism?

Answer 7

It stimulates RANKL expression and thus bone resorption.

Question 8

What is the MOA of prostaglandin E2 on bone metabolism?

Answer 8

It activates adenylyl cyclase and thus increases bone resorption.

Question 9

List 5 molecules that inhibit bone resorption (decrease osteoclast activity):

Answer 9

• osteoprotegerin (OPG)
• calcitonin
• estrogen (via decreased RANKL)
• transforming growth factor beta (via increased OPG)
• interleukin 10 (IL-10)

Question 10

What is the mechanism of action of osteoprotegerin (OPG)?

Answer 10

• it is a decoy receptor produced by osteoblasts and stromal cells that binds to and sequesters RANKL
• it inhibits osteoclast differentiation, fusion and activation

Question 11

What is the MOA of calcitonin on bone metabolism?

Answer 11

It interacts directly with the osteoclast via cell-surface receptors, inhibiting bone resorption.

Question 12

What is the MOA of estrogen on bone metabolism?

Answer 12

• Stimulates bone production (anabolic) and prevents resorption.
• inhibits activation of adenylyl cyclase pathway.

Question 13

What is the MOA of IL-10 on bone metabolism?

Answer 13

It suppresses osteoclasts.

Question 14

What is osteopetrosis and what is one theory on its underlying pathophysiology?

Answer 14

• osteopetrosis is a condition caused by a genetic defect, resulting in absence of osteoclastic bone resorption.
• a mouse RANKL knockout model creates an osteopetrosis-like condition.

Question 15

How is osteolytic bone metastasis mediated, and how can it be improved?

Answer 15

• mediated by the RANK/RANKL pathway
• blocking of RANKL by OPG results in decreased skeletal metastasis in animal models
• bisphosphonates decrease skeletal events in cancer metastasis

Question 16

Bone metabolism is a dynamic process that balances ____

Answer 16

Bone formation and bone resorption.

**use advanced editor to put photo of rank/RANKL diagram